title: The Semaphorin 4D-Plexin-B1-RhoA signaling axis recruits pericytes and regulates vascular permeability through endothelial production of PDGF-B and ANGPTL4.
abstract: Semaphorin 4D (SEMA4D) is a member of a family of transmembrane and secreted proteins that have been shown to act through its receptor Plexin-B1 to regulate axon growth cone guidance, lymphocyte activation, and bone density. SEMA4D is also overexpressed by some malignancies and plays a role in tumor-induced angiogenesis similar to vascular endothelial growth factor (VEGF), a protein that has been targeted as part of some cancer therapies. In an attempt to examine the different effects on tumor growth and vascularity for these two pro-angiogenic factors, we previously noted that while inhibition of both VEGF and SEMA4D restricted tumor vascularity and size, vessels forming under conditions of VEGF blockade retained their association with pericytes while those arising in a background of SEMA4D/Plexin-B1 deficiency did not, an intriguing finding considering that alteration in pericyte association with endothelial cells is an emerging aspect of anti-angiogenic intervention in the treatment of cancer. Here we show through array analysis, immunoblots, migration and co-culture assays and VE-cadherin immunohistochemistry that SEMA4D production by head and neck carcinoma tumor cells induces expression of platelet-derived growth factor-B and angiopoietin-like protein 4 from endothelial cells in a Plexin-B1/Rho-dependent manner, thereby influencing proliferation and differentiation of pericytes and vascular permeability, whereas VEGF lacks these effects. These results partly explain the differences observed between SEMA4D and VEGF in pathological angiogenesis and suggest that targeting SEMA4D function along with VEGF could represent a novel anti-angiogenic therapeutic strategy for the treatment of solid tumors.
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650 West Baltimore Street, 7-North, Baltimore, MD, 21201, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Yang
authors.forename: John R
authors.initials: JR
authors.lastname: Basile
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000096:biosynthesis* / Q000235:genetics; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020286:Pericytes / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000096:biosynthesis* / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D015703:Antigens, CD; C093224:CD100 antigen; D009419:Nerve Tissue Proteins; C492119:PLXNB1 protein, human; D020574:Proto-Oncogene Proteins c-sis; D011956:Receptors, Cell Surface; D039961:Semaphorins; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein